The overall objective of this research is to develop new chemotherapeutic approaches to the treatment of African sleeping sickness, South American trypanosomiasis (Chagas' disease) and the leishmaniases. The first aim is to synthesize inhibitors of the enzymes farnesyl pyrophosphate synthase (FPPS) and geranylgeranylpyrophosphate synthase (GGPPS), key enzymes of the mevalonate (isoprene) pathway. The hypotheses to be tested are that bisphosphonates and related compounds are inhibitors of the FPPS and GGPPS enzymes and they represent novel anti-parasitic agents. The rationale for this work is that we have found that many bisphosphates inhibit the growth of the parasitic protozoa T. cruzi, T. brucei rhodesiense, L. mexicana, and L. donovani and effect parasitological cures of L. mexicana amazonensis and L. donovani infections in Balb/c mice and 90 percent reductions in parasitemia with T. cruzi. FPPS has been identified as one of the drug targets and an expressed T. cruzi FPPS has been shown to be potently inhibited by bisphosphonates, including those currently used in bone resorption therapy. The second aim is to test the antiparasitic activity of phosphonate based drugs in vitro and in vivo and use this information for drug design. The drugs will be tested for activity against recombinant FPPS from T. cruzi and T. brucei and GGPPS of L. major, in established in vitro screening systems and in animal models of leishmaniasis, as well as T. brucei and T. cruzi infections. The third aim is to optimize the use of bisphosphonate drugs as antiparasitic agents via combination therapy with other inhibitors of the mevalonate pathway and to optimize drug delivery (liposomal, polymer and pro-drug approaches), leading to more efficient and/or more practical therapies.